IE921376A1 - Pyrrolidinones - Google Patents

Info

Publication number

IE921376A1

IE921376A1 IE137692A IE921376A IE921376A1 IE 921376 A1 IE921376 A1 IE 921376A1 IE 137692 A IE137692 A IE 137692A IE 921376 A IE921376 A IE 921376A IE 921376 A1 IE921376 A1 IE 921376A1

Authority

IE

Ireland

Prior art keywords

formula

cyclopentyloxy

substituted

compound

mmol

Prior art date

1991-05-02

Links

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• Global Dossier
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• 150000004040 pyrrolidinones Chemical class 0.000 title abstract description 3
• 150000001875 compounds Chemical class 0.000 claims description 225
• -1 2-imidazolyl Chemical group 0.000 claims description 71
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 66
• 238000006243 chemical reaction Methods 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 49
• 239000001257 hydrogen Substances 0.000 claims description 46
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 38
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 36
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 150000002431 hydrogen Chemical group 0.000 claims description 24
• 238000000034 method Methods 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 22
• 235000019000 fluorine Nutrition 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 19
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 15
• 230000002401 inhibitory effect Effects 0.000 claims description 15
• 238000004519 manufacturing process Methods 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 14
• 230000005764 inhibitory process Effects 0.000 claims description 13
• 229910052794 bromium Inorganic materials 0.000 claims description 12
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 10
• CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 230000009467 reduction Effects 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 8
• 230000008569 process Effects 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• 229910052740 iodine Inorganic materials 0.000 claims description 7
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
• 208000026935 allergic disease Diseases 0.000 claims description 6
• 230000000172 allergic effect Effects 0.000 claims description 6
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 6
• 208000027866 inflammatory disease Diseases 0.000 claims description 6
• 230000001404 mediated effect Effects 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000006239 protecting group Chemical group 0.000 claims description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
• 239000000460 chlorine Substances 0.000 claims description 5
• 229910052801 chlorine Inorganic materials 0.000 claims description 5
• 125000001309 chloro group Chemical class Cl* 0.000 claims description 5
• 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 125000002971 oxazolyl group Chemical group 0.000 claims description 5
• 125000005592 polycycloalkyl group Polymers 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 125000001425 triazolyl group Chemical group 0.000 claims description 5
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
• 239000002168 alkylating agent Substances 0.000 claims description 4
• 229940100198 alkylating agent Drugs 0.000 claims description 4
• 150000001408 amides Chemical class 0.000 claims description 4
• 239000003054 catalyst Substances 0.000 claims description 4
• 235000017168 chlorine Nutrition 0.000 claims description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
• 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 3
• 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 3
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000005842 heteroatom Chemical group 0.000 claims description 3
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• GMTVBECLHDYSRJ-UHFFFAOYSA-N n-[3-acetamido-4-[[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C(C2CC(=O)N(CC=3C(=CC(NC(C)=O)=CC=3)NC(C)=O)C2)C=C1OC1CCCC1 GMTVBECLHDYSRJ-UHFFFAOYSA-N 0.000 claims description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
• MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 230000018044 dehydration Effects 0.000 claims description 2
• 238000006297 dehydration reaction Methods 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims description 2
• 150000002466 imines Chemical class 0.000 claims description 2
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
• SUXHVTWOXBFQIA-FQEVSTJZSA-N n-[4-[[(4r)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C([C@H]2CC(=O)N(CC=3C=CC(NC(C)=O)=CC=3)C2)C=C1OC1CCCC1 SUXHVTWOXBFQIA-FQEVSTJZSA-N 0.000 claims description 2
• 229910052717 sulfur Inorganic materials 0.000 claims description 2
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
• 229930192474 thiophene Natural products 0.000 claims description 2
• IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 claims description 2
• 230000009466 transformation Effects 0.000 claims description 2
• 102000003390 tumor necrosis factor Human genes 0.000 claims 6
• 230000002265 prevention Effects 0.000 claims 2
• DBRURKICGBSTER-GOSISDBHSA-N (4s)-1-[(4-aminophenyl)methyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one Chemical compound COC1=CC=C([C@@H]2CC(=O)N(CC=3C=CC(N)=CC=3)C2)C=C1OC1CCCC1 DBRURKICGBSTER-GOSISDBHSA-N 0.000 claims 1
• KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims 1
• CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims 1
• SUXHVTWOXBFQIA-HXUWFJFHSA-N n-[4-[[(4s)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C([C@@H]2CC(=O)N(CC=3C=CC(NC(C)=O)=CC=3)C2)C=C1OC1CCCC1 SUXHVTWOXBFQIA-HXUWFJFHSA-N 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 228
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 220
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
• 239000000243 solution Substances 0.000 description 128
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 103
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
• 239000002904 solvent Substances 0.000 description 88
• 229910001868 water Inorganic materials 0.000 description 80
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 78
• 239000000203 mixture Substances 0.000 description 67
• 238000004458 analytical method Methods 0.000 description 59
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
• 238000003818 flash chromatography Methods 0.000 description 52
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
• 239000012300 argon atmosphere Substances 0.000 description 47
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 44
• 239000012044 organic layer Substances 0.000 description 44
• 229910052938 sodium sulfate Inorganic materials 0.000 description 44
• 235000011152 sodium sulphate Nutrition 0.000 description 44
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• 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 32
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• 229910000027 potassium carbonate Inorganic materials 0.000 description 29
• 239000000284 extract Substances 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
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• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 23
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• 239000003921 oil Substances 0.000 description 23
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• HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 9
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